Intermediates for preparation of 2,3-trans-1,4-bridged cyclohexane sulfonamide derivatives

ABSTRACT

A process suitable for industrially preparing 2,3-trans-1,4-bridged cyclohexane sulfonamide derivatives, especially useful as an intermediate for the synthesis of a trans bicyclo[2,2,1] heptane carboxylic acid derivative, a clinically important thromboxane A 2  antagonist, comprising: allowing to react corresponding a cis/trans mixture of sulfonamide derivatives with an anionoid or water-soluble carbonyl reagent at pH 3-7 so that the trans isomer may form a water-soluble adduct with the anionoid or carbonyl reagent, separating the resulting adduct dissolved in an aqueous layer, and recovering the trans isomer by treating the adduct with a base or an acid. Also provided is an alkali metal hydrogen sulfite adduct of 2,3-trans 1,4-bridged cyclohexane sulfonamide derivative.

This application is a division of application Ser. No. 711,562, filedMay 30, 1991 now U.S. Pat. No. 5,120,865 which application is acontinuation of now abandoned application Ser. No. 447,520, filed Dec.7, 1989.

This invention relates to a process for preparing 2,3-trans-1,4-bridgedcyclohexane sulfonamide derivatives which are useful as an intermediatefor the preparation of clinically important thromboxane A₂ antagonist.More particularly, it relates to a process for stereoselectivelypreparing the intermediate of the formula (I): ##STR1## wherein R isphenyl or phenyl substituted with hydroxy, lower alkoxy, halogen orlower alkyl; Y is methylene, substituted methylene, ethylene, vinyleneor oxygen; m is 0 or 1; n is 0, 1 or 2 with proviso that when m is 0, nis not 0, and when m is 1, n is not 2.

Thromboxane A₂, referred to as TXA₂ hereinafter, is a member ofprostanoids which are biologically active substances and synthesizedenzymatically from eicosapolyenoic acids, such as arachidonic acid invarious animal tissues, for example, platelets, vascular walls, and thelike. TXA₂ has been proved to exhibit many significant biologicalactivities, such as aggultination of platelets and contraction of smoothmuscle of various organs, e.g., bronchus, coronary artery, pulmonaryartery, and the like, at a relatively low serum level of about 10⁻¹¹ -10⁻¹² M. Because of these biological activities, TXA₂ has beenconsidered to be one of the major causes of myocardial infarction,cerebral infarction, bronchial asthma, and thrombosis. Therefore, TXA₂synthetase inhibitors which inhibit an enzyme responsible for thebiosynthesis of TXA₂, or TXA₂ receptor antagonists which antagonize thebinding of TXA₂ to its receptor, have been expected to be practicallyuseful in the treatment and prevention of the above-mentioned diseases.However, the inhibitors are not suited for clinical use becauseinhibition of TXA₂ synthesis may result in accumulation of theprecursor, i.e., prostaglandin H₂, which is believed to exhibit abiological activity similar to that of TXA₂. To the contrary, thereceptor antagonists are thought to be useful for treating andpreventing TXA₂ -dependent diseases because they are not affected by theaccumulated prostaglandin H₂.

In view of the above, the present inventors made extensive study andfound that 1,4-bridged cyclohexane carboxylic acid derivatives, whichare analogous compounds to TXA₂ or prostaglandin H₂, serve as anantagonist against TXA₂ and are chemically and biochemically stable[see, Japanese Patent Publication (Kokai) No. 139161/1988]. Theinventors have continued the study in order to obtain more effectiveantagonists and found that trans isomers of said compounds are superiorto cis isomers. The trans isomers are shown in the following generalFormula (II): ##STR2## wherein R, Y, m, n have the same meanings asdefined above, and q is 3 or 4.

The compounds above can be prepared according to the afore-mentionedJapanese patent publication, for example, the compound in which R isunsubstituted phenyl, Y is methylene, m is 1, n is 0, and q is 3, isprepared in the manner as described below starting from the compound ofFormula 1: ##STR3##

Specifically, an amine of Formula 2: ##STR4## is first prepared from theabove ketone 1 by introducing an allyl group at the 2-position,converting the carbonyl group at the 3-position into oxime, and reducingsaid oxime to an amino group giving a trans/cis mixture. Afterprotection of the amino group, the amine 2 is oxidized at the allylgroup giving an epoxide. The latter gives a trans/cis mixture ofaldehydes of the following Formula 3 by oxidative cleavage: ##STR5##wherein Z is an amino-protecting group. The aldehyde 3 is then reactedwith an ylide under reaction conditions of the Wittig Reaction. Theresultant product is then esterified and deprotected withtri-fluoroacetic acid and anisole to give a free amine, which is thensulfonated with sulfonyl halide, such as phenylsulfonyl chloride, toform a trans/cis mixture of bicyclo[2,2,1]heptane carboxylic acidsulfonamide derivatives.

In order to obtain the trans isomer of the product, the mixture can beseparated, for example, by chromatography on silica-gel. Alternatively,the intermediate aldehyde of Formula 3 can be separated in advance toobtain the trans isomer, which may be employed in the subsequent steps.

As can be seen from the above description, the previous procedures aretoo complicated to apply to an industrial mass-production of the desiredtrans carboxylic acid derivatives. In particular, the step for theseparation of the trans isomer from the cis isomer effected bychromatography is time-consuming and also uneconomical. Therefore, ithas been needed to establish a more simple and economical process forpreparing the trans isomer of the afore-mentioned carboxylic acidderivatives.

The inventors have found (i) that a mixture of trans/cis compounds ofFormula (I)': ##STR6## wherein R, Y, m and n have the same meanings asabove, is easily produced by ozonolysis of a sulfonamide derivative ofamine 2 at the allyl position, followed by treatment withtriphenylphosphine, and (ii) that the trans isomer of the compound (I)'can form a reversible water soluble adduct (salt) upon treating with ananionoid reagent or a water-soluble carbonyl reagent, whereas the cisisomer can not, whereby both isomers can be separated from each other onthe basis of the difference of their solubilities in an aqueous medium,and (iii) that as a result the trans isomer of the compound (I)' can beeasily converted into the final trans carboxylic acid derivative. Thepresent invention has been accomplished on the basis of those findingsabove.

Thus, this invention provides a process for preparing a2,3-trans-1,4-bridged cyclohexane sulfonamide derivative of Formula (I),which comprises the steps:

(a) reacting a cis/trans mixture of 1,4-bridged cyclohexane sulfonamidesof Formula (I)': ##STR7## wherein R, Y, m, and n are as defined above,in a mixture of water and an organic solvent at pH 3-7 with an anionoidreagent or a water-soluble carbonyl reagent, which forms a water-solubleadduct only with the trans isomer of said sulfonamide (I)';

(b) separating an aqueous layer containing the water-soluble transisomer in the form of the adduct from an organic layer containing thewater-insoluble cis isomer; and

(c) recovering the said trans isomer (I) by treating the aqueous layerobtained in step (b) with a base or an acid.

For the purpose of the present invention, as disclosed and claimedherein, the following terms are defined as below.

The term "lower alkyl" refers to a straight or branched saturatedhydrocarbon radical having one to eight carbon atoms, including methyl,ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, 1-methylbutyl, 1,2-dimetylbutyl, hexyl,heptyl, octyl, and the like.

The term "lower alkoxy" refers to C₁ -C₈ alkoxy, including methoxy,ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexyloxy, heptyloxy, andoctyloxy, and the like.

The term "substituted methylene" refers to ethylidene,dimethylmethylene, methylethylmethylene, diethylmethylene, or the like.

The term "halogen" refers to chlorine, bromine, iodine and fluorine.

The term "alkali metal" refers to lithium, potassium or sodium.

The preferred examples of R are phenyl, o-tolyl, m-tolyl, p-tolyl,4-ethylphenyl, 4-pentylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl,4-fluorophenyl, 4-bromophenyl, and 4-chlorophenyl. The preferredexamples of Y are methylene, dimethylmethylene, ethylene, vinylene andoxygen.

Particularly preferred sulfonamide derivatives of Formula (I) are thecompounds (I) wherein R is phenyl, p-tolyl, 4-hydroxyphenyl or4-bromophenyl; Y is methylene or oxygen; and m is 1, n is 0, or m is 0,n is 1.

The trans/cis sulfonamide derivatives (I)', the starting material of thepresent invention, can be prepared by cleaving the correspondingcompounds having an unsaturated alkyl such as an allyl group at the2-position in the manner as disclosed in the afore-mentioned JapanesePatent Publication.

Anionoid or carbonyl reagents which can be used as a resolving agent inthe method of the present invention are selected from those capable offorming a water-soluble adduct with a formyl group of the compound (I).Typical anionoid reagents are metal-hydrogen sulfites, such as sodiumhydrogen sulfite and sodium cyanide. Typical soluble carbonyl reagentsare Girard reagents T and P. Anionoid reagents, especially sodiumhydrogen sulfite, are preferred in the process of the present invention.

According to the present invention, the starting compound (I)' isreacted with a selected anionid or carbonyl reagent using known reactionconditions in the art. The compound (I)' may be reacted with an anionoidreagent in a molecular ratio of 1:1-1:10 in a solvent containing waterand a relatively inert organic solvent, such as dichloromethane, inwhich aqueous layer has been adjusted to pH 3-7, preferably about pH 4.Alternatively, the solvent used for the proceeding ozonolysis reactioncan be used as such to make the reaction more convenient. Temperature inthe range of about 0° C.-40° C. may be employed with a preferredtemperature being about 20° C.±5° C. Under these conditions, the transisomer of the compound (I)' forms a water-soluble adduct with theselected resolving agent, while the cis isomer remains unchanged. Theorganic layer containing the latter is separated from the aqueous layerand the organic layer is extracted with water again. The aqueousextracts are combined, and the free aldehyde (I) is recovered from thecombined aqueous phase by conventional methods. For example, the aqueousphase containing the adduct is treated with a base to release the freealdehyde, which is then extracted with a water-immiscible solvent suchas dichloromethane, in which the trans isomer is soluble.

The process of the invention provides a high degree of separation of thetrans isomer (I) from not only the cis-isomer but also othernon-aldehydes, as reflected by its purity. Thus, the trans isomer (I)which has been obtained by evaporating the solvent to dryness has morethan about 99% purity.

The process of the present invention as detailed in the above isapplicable to any compounds described in the afore-mentioned JapanesePatent Publication, provided that their trans isomers can form awater-soluble adduct with an anionoid reagent or a carbonyl reagent,while cis isomers fail to form an adduct under the reaction conditiondescribed above.

The adducts of the trans isomer with an anionoid reagent are novel, andcan be shown by the following Formula (III): ##STR8## where R, Y, m andn are as defined above, and M is an alkali metal. The adducts can beeasily decomposed to give the desired free aldehyde of Formula (I) byaddition of a base such as sodium hydroxide.

As previously mentioned, sodium hydrogen sulfite is a preferred anionoidreagent. The metal hydrogen sulfite adduct of 2,3-trans-1,4-bridgedcyclohexane sulfonamide of Formula (III) is especially useful amongothers as an intermediate for the mass production of the final transcarboxylic acid derivative which exhibits a potent antagonistic actionagainst TXA₂. Thus, as a further aspect of the invention, there areprovided the novel compounds of Formula (III), inter alia, the compound(III) wherein M is sodium.

The following example is set forth to further describe the invention butin no way meant to be construed as limiting the scope thereof.

EXAMPLE 1 (2S*)-2-Exo-3-endo-2-formylmethyl-3-phenylsulfonylamino-bicyclo[2,2,1]heptaneA. Reaction ##STR9##

8.0 g (27 mmol) of sulfonamide (Va) is dissolved in a mixture of 6 ml ofmethanol and 100 ml of dichrolomethane, and cooled to -65° C. To thesolution was introduced 1.18 equivalents of theoretically necessaryamounts of ozone at -60° C. over 1 hr. After removal of the excess ofozone from the reaction mixture by introducing N₂ gas at the sametemperature for 10 minutes, 8.6 g (1.2 eq.) of (Ph)₃ P in 12 ml ofdichloromethane is added dropwise to the mixture at -60° C. over 10minutes. The resulting mixture is gradually warmed up to 0° C. over 15minutes and allowed to stand for 3 hr at the same temperature. Thereaction mixture is poured into 40 ml of a 1% aqueous sodium thiosulfatesolution. The organic layer is separated and the aqueous layer isextracted with dichloromethane. After washing 2 times with water, thedichloromethane layers containing the trans/cis mixture of compound(IIa) are combined.

B. Separation ##STR10##

To the dichloromethane solution containing compound (IIa) is added 60 ml(3 eq.) of a 17.5% aqueous solution of sodium hydrogen sulfite and themixture is stirred at 20° C. for 30 minutes. The mixture is separatedand the organic solution is extracted with water, and the water extractscontaining (IIIa) are washed with dichloromethane and combined(dichloromethane layers containing the compound (IVa) are discarded).The aqueous solution is mixed with 70 ml of dichloromethane and cooledto 5° C. To the cooled solution is added dropwise over about 1 hr 17 ml(3 eq.) of a 24% NaOH solution previously cooled to 10° C., while thereaction temperature being maintained at 5° C. (pH÷11). The mixture isseparated and the aqueous layer is extracted with dichloromethane. Theorganic solutions are washed with water (×3), combined, and concentratedto dryness under reduced pressure to obtain 9 g of the crude titledtrans sulfonamide. Recrystallization from ether-petroleum ether givescompound (Ia). Yield=6.84 g (85%). M.p.=83.8°-84.8° C.

In the same manner as above, optically active (Ia) is obtained fromoptically active (Va). M.p.=100°-103° C.

[α]_(D) =+36.5±0.8° (CHCl₃, C=0.994%, 25.5° C.) Physico-chemicalproperties of intermediates (IIIa) and (IVa) are shown below:

(IIIa);

IRγmax (Nujol): 3100-3500 (broad), 1640, 1320, 1150, 1100, 1040, 950,890 cm⁻¹

cis formyl compound (IVa);

NMR (CDCl₃) δppm: 0.9-1.3 (6 H, m), 1.52 (1 H, m), 1.8-2.0 (1 H, m),2.06 (1 H, dd, J=9.1, 13.5 Hz), 2.3-2.4 (1 H, m), 2.4-2.5 (1 H, m), 3.26(1 H, dd, J=2, 2.6 Hz), 3.65 (1 H, dd, J=1.2, 7.6 Hz), 5.47 (1 H, dd,J=2.6, 5 Hz), 7.5-7.7 (3 H, m), 7.8-7.95 (2 H, m).

What we claim is:
 1. Alkali metal hydrogen sulfite salt of2,3-trans-1,4-bridged cyclohexane sulfonamide derivative of Formula(III): ##STR11## where R is phenyl or phenyl substituted with hydroxy,lower alkoxy, halogen or lower alkyl; Y is unsubstituted or substitutedmethylene, ethylene, vinylene or oxygen; m is 0 or 1; n is 0, 1 or 2with the proviso that when m is 0, n is not 0, and when m is 1, n is not2; and M is an alkali metal.
 2. The salt of claim 1 wherein M is sodium.